Q&A: Single oral immunotherapy desensitizes children to multiple food allergens

Key takeaways:

• ADP101 includes 15 substances from the nine most common food allergens.
• 56% of participants with multiple allergies on the high dose of ADP101 achieved desensitization to two or more foods.

ANAHEIM, Calif. — Children with allergies to multiple foods achieved desensitization with a multi-food oral immunotherapy, according to a study presented at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting.

ADP101 (Alladapt Immunotherapeutics) is a dry powder mixture that includes 15 drug substances representing the nine most common allergens, which account for 90% of severe food reactions among patients with food allergy.

Among 61 children with 123 qualifying food allergies in the Harmony study, 55% of those taking high doses of ADP101 and 38.1% of those taking low doses had responded to the therapy by 40 weeks, compared with 20% in the placebo group.

Also, the FDA has granted ADP101 a fast track designation, which will expedite its development as a treatment for food allergy including more frequent meetings and written communications with the FDA, in addition to rolling and priority reviews.

Healio spoke with Ashley Dombkowski, PhD, CEO and cofounder of Alladapt Immunotherapeutics, to find out more about ADP101 and the study.

Healio: What are the limitations of current OIT treatments?

Dombkowski: The standard of care for food allergy is constant, meticulous avoidance of consumption/contact with allergens along with the use of rescue epinephrine in the event of a reaction caused by exposure. There is a single FDA-approved treatment for food allergy, which happens to be an OIT. This treatment is indicated exclusively for the treatment of peanut allergy in children and, while quite effective, commercial uptake has been slow based on two limitations.

First, mono-allergy to peanut is relatively rare among patients with uncontrolled food allergy seeking treatment. For example, among patients seen in the ED for food allergy reactions over a 12-month period, 93% were either multi-allergic or allergic to foods other than peanut. Second, the existing approved dosing protocol requires an initial dose escalation day in which patients receive five increasing doses of drug over a 4-hour visit, which is an arduous, symptomatic and time-consuming experience.

There are also a number of settings that offer home-brew OIT. Most allergists have not embraced this approach due to practice liability from non-FDA-approved treatment and concerns about patient risk. Among businesses that do offer home-brew, protocols are nonstandardized, allergen consistency and quality is not assessed or documented, patients and parents are often required to source and measure doses on their own, multi-food allergy is usually approached by treating each allergy sequentially over the course of several years, common and difficult allergens such as seafood are rarely offered, and clinicians are not always involved.

That being said, in the cases of environmental allergy and insect venom allergy, allergen immunotherapy is an established interventional precedent that is considered both effective and disease modifying. OIT for the treatment of food allergy may offer similar mechanistic promise for delivering not only desensitization but long-term disease-modifying benefits. Our goal at Alladapt is to successfully develop an FDA-approved treatment for patients with mono- or multi-food allergy that can deliver on the promise that OIT has shown to remodel the allergic response to allergens and lower patient burden of this disease.

Healio: How does ADP101 address these limitations?

Dombkowski: Alladapt’s ability to address these limitations is based on two primary differentiators.

First, we are developing ADP101 as a well-characterized, consistent, premeasured, pharmaceutical-grade OIT formulated to simultaneously address mono- or multi-allergy to any or all of the world’s 15 most significant food allergens: almond, cashew, chicken’s egg, codfish, cow’s milk, hazelnut, peanut, pecan, pistachio, salmon, sesame, shrimp, soy, walnut and wheat. This breadth of coverage would address the majority of patients with high unmet need and poorly controlled food allergy rather than the small minority seeking treatment for peanut allergy alone.

Second, we have designed an optimized and proprietary “low and slow” dosing protocol to deliver an improved patient experience and to streamline the clinic workflow. This protocol showed excellent safety and tolerability in the Harmony study. It also replaced the concept of an arduous initial dose escalation day with a gentle initial dosing day that only requires patients to receive a single ultra-low dose on day 1.

Together, our formulation and careful dosing strategy position ADP101 to emerge as a transformative solution in the field of OIT for food allergy.

Additionally, there are multiple mechanistically complementary drugs that could be developed for use in food allergy as adjuvant treatment alongside OIT. This includes anti-IgE, Bruton tyrosine kinase inhibition, anti-thymic stromal lymphopoietin and other approaches. As a broadly applicable, FDA/EMA-approved OIT, ADP101 would be an ideal backbone for combination in such applications.

Healio: Could you provide some details about the participants in this study?

Dombkowski: The phase 1/2 Harmony study studied the safety and efficacy of ADP101 in promoting desensitization among patients with single or multiple food allergies. The trial enrolled 61 people aged 4 to 17 years in the pediatric group, and 12 people aged 18 to 55 years in the exploratory adult group. To participate in the trial, people had to have a confirmed allergy to one to five foods included in ADP101 with an eliciting dose of 100 mg or less of allergenic protein as determined by a double-blind, placebo-controlled food challenge. Patients were randomly assigned using a 2:2:1:1 ratio to receive high-dose ADP101, low-dose ADP101, high-dose placebo or low-dose placebo. Also, 67% were male and 33% were female, and 67% identified as white, 20% Asian, 5% Black and 8% other.

There was broad representation of allergens in Harmony, with allergy to each and every one of the 15 allergens covered by ADP101 observed and with an average eliciting dose of just 30 mg of protein per allergen. There was also a strong history of reactivity. For example, 67% of children had a history of anaphylaxis. Additionally, we saw a remarkable diversity of disease presentations. Among the study’s 61 children, 31 distinctive combinations of allergens were observed spanning a range of mono- and multi-allergy.

Healio: How did you define response to therapy?

Dombkowski: Response was defined as a participant’s ability on double-blind, placebo-controlled exit food challenge to demonstrate a meaningful increase in their ability to tolerate one or more of their allergens. This specifically meant that a patient needed to consume a single dose of 600 mg or more of protein from their allergen without experiencing dose-limiting symptoms.

Note that consuming a single dose of 600 mg of protein is equivalent to a cumulative dose of 1,044 mg of protein in a single day, given that patients are required to start with smaller amounts. In the case of peanut, independent researchers have found that improving the threshold of reactivity from 100 mg or less to just 300 mg of peanut protein may reduce the risk for experiencing an allergic reaction from common sources of peanut contamination by more than 95%.

Healio: Are there any other specific data pertaining to efficacy that you would like to include?

Dombkowski: We also are excited to see consistent dose-dependent efficacy trends in our secondary endpoints. We saw that approximately 56% of patients on high-dose ADP101 were desensitized to two or more foods simultaneously vs. none of the patients on placebo after just 40 weeks of treatment. What’s more, 44% of patients receiving high-dose ADP101 were desensitized to 1,000 mg (2,044 mg cumulative) or more of two or more food allergens compared with a 0% response rate among patients on placebo. For context, 1,000 mg is about four peanuts. The fact that we are seeing these responses simultaneously after less than a year is very encouraging and something we would like to further explore.

Alladapt is also conducting the Encore study, an open-label extension study of the Harmony study assessing long-term use of ADP101. In addition to safety and tolerability data, Encore is assessing potential for improved response rates overall, a breadth of responses seen across allergens, and increases in the magnitude of desensitization experienced by patients over time. Data from Encore are expected to be reported on an annual basis, with the first results anticipated in early 2024.

Healio: Adverse events were mostly mild or moderate. Could you provide more details?

Dombkowski: ADP101 was well-tolerated in the Harmony trial. Most incidences of treatment-emergent adverse events were categorized as mild or moderate, and rates diminished as patients moved from up-dosing into maintenance dosing. In the subsequent dose-maintenance period, the occurrence of adverse events with a frequency exceeding 15% in any treatment group was notably absent.

Also, there were no recorded occurrences of severe anaphylactic reactions associated with ADP101, and no study participants on ADP101 discontinued the study due to anaphylaxis. The administration of epinephrine for patients on active therapy occurred primarily during up-dosing and was associated with the management of mild or moderate reactions. The study discontinuation rate due to adverse events was 5% whether patients were on active therapy or placebo.

Healio: Could you provide some details about the upcoming phase 3 program?

Dombkowski: In our phase 3 program, we plan to evaluate the safety and efficacy of ADP101 in children aged between 4 and 17 years with one or more food allergy over the course of 1 year. Striving for optimal efficacy without compromising safety or tolerability remains our goal, and we plan to have one active treatment arm and a corresponding placebo arm.

These patients will be required to exhibit allergic reactions to at least one, and potentially more, of the foods covered, which includes almond, cashew, chicken’s egg, codfish, cow’s milk, hazelnut, peanut, pecan, pistachio, salmon, sesame, shrimp, soy, walnut and wheat. We anticipate unequal distribution of allergens could occur across the study population based on epidemiology, in so far as some allergens have higher prevalence than others. This may prompt us to implement targeted recruitment strategies, though the details remain to be finalized.

We are projecting a maintenance period of 6 months, with 11 dosing levels aimed at bringing patients to the maintenance phase. The fastest pace for patients to progress through these up-dosing steps would be every 2 weeks, although the protocol is being designed to be patient-centric and allow customizations.

For example, some patients may progress at a slower pace or even down-dose during periods of heightened immune system activity, such as viral infections or environmental allergy seasons, before resuming up-dosing.

This flexibility in dosing aims to enhance patient comfort and support overall tolerability within the protocol. This feature was highlighted as a significant differentiator, appreciated by both patients and clinicians during the Harmony study, and, thus, it will be retained in our upcoming research.
We are pleased to have received fast track designation from FDA in late November, which will allow us to engage even more actively with the FDA to refine our clinical plans. We hope to be able to share more about the phase 3 clinical trial endpoints and other aspects of the study design soon.

References:

• Alladapt Immunotherapeutics receives FDA fast track designation for ADP101 for the treatment of mono- and multi-food allergies. https://assets-global.website-files.com/5e4aeee404e0b868e6d9f7f0/655d803cea26f680dd87d6c9_Alladapt%20%E2%80%93%20FDA%20Fast%20Track%20%E2%80%93%2022-NOV-2023.pdf. Published Nov. 22, 2023. Accessed Nov. 22, 2023.
• Baumert JL, et al. J Allergy Clin Immunol Pract. 2018;doi:10.1016/j.jaip.2017.05.006.
• Carr WW, et al. P180. Presented at: ACAAI Annual Scientific Meeting; Nov. 9-13, 2023; Anaheim, California.
• Warren CM, et al. Ann Allergy Asthma Immunol. 2023;doi:10.1016/j.anai.2022.12.031.